GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study

Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma. Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma. Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated. Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype. Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution. Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424; http://dx.doi.org/10.1289/ehp.1307459


Appendix S1. Cohort Descriptions
The Canadian Asthma Primary Prevention Study (CAPPS) is a prospective, randomized controlled study with follow-up to the age of 7 years. 545 high-risk infants were randomized prior to birth in the study centers of Vancouver and Winnipeg, Canada. High-risk was defined as having one first-degree relative with asthma or two first-degree relatives with other IgE mediated diseases. The multifaceted intervention included education and counseling on the risk factors of asthma, specifically dust mite and environmental tobacco smoke avoidance, and breastfeeding support. Parents completed questionnaires on respiratory symptoms and physician diagnoses at 1, 2 and 7 years. At 7 years children were examined by a pediatric allergist blinded to intervention status and questionnaire responses; and peripheral blood was obtained from children and their parents. Asthma was defined from questionnaires as at least two of more distinct episodes of cough (each lasting a minimum of 2 weeks), at least two distinct episodes of wheeze (each lasting a minimum of 1 week), plus at least one of the following: nocturnal cough at least once per week (in absence of a cold), hyperpnoea-induced cough or wheeze at any time, or response to treatment with β-agonist and/or anti-inflammatory drugs (Chan-Yeung et al. 2000;Carlsten et al. 2011).
The Study of Asthma, Genetics and Environment (SAGE) is a population-based birth cohort.
Children were identified for inclusion from a provincial healthcare registry. The study included all 13,980 children born in the province of Manitoba in 1995 with continued residence in the province through 2002. Surveys were sent to each family when children were 7 years old and, from the 3,598 responders, 723 children were selected for a nested case-control study of asthma (246 asthmatics; 477 controls). Children living in rural areas, low-income neighborhoods and First Nations communities were over-sampled. At mean age of 9 years, children were examined by a pediatric allergist for allergic diseases, including asthma, and symptoms (Kozyrskyj et al. 2009).
The Children, Allergy, Milieu, Stockholm, Epidemiological Survey (BAMSE) is a population based prospective birth cohort study with follow-up through the age of 16. Between February 1994 and November 1996 newborns were recruited at their first child health visit in predefined areas of Stockholm,Sweden (n = 4,089). Infants were excluded if their family was planning to move during the first year of life, an older sibling was already enrolled, serious illness during the neonatal period or parents had insufficient knowledge of Swedish. Parental questionnaires were used to assess physician diagnosed asthma, allergic rhinitis and eczema; and episodes of wheezing at ages 1, 2, 4 and 8 years (Wickman et al. 2002). At 4 years of age 2,298 children provided blood samples and a sub-sample of this group was used to populate a nested case-control study of wheeze (497 wheezers; 485 randomly selected controls) (Melén et al. 2008).
The German infant study on the influence of nutrition intervention plus environmental and genetic influences on allergy development (GINIplus) is a population based prospective birth cohort, with an intervention component and follow-up to the age of 15 years. Between September 1995-June 1998 parents attending one of 18 maternity hospitals in the cities of Munich or Wesel were invited to participate. A total of 5,991 healthy full-term newborns whose parents were fluent in German were recruited. A subgroup of 2,252 infants with at least one atopic parent or sibling were assigned to the intervention group and randomly allocated to one of four study formulas if their parents chose not to breastfeed. Parental questionnaires were used to assess physician diagnosed asthma, allergic rhinitis and eczema; and episodes of wheezing at ages 1, 2, 3, 4, 6 and 10 years (Gehring et al. 2002).
Clinical examinations and blood samples for DNA extraction were obtained at 6 and 10 years.
The influence of life style factors on the development of the immune system and allergies in East and West Germany plus the influence of traffic emissions and genetics (LISAplus) study is a population based prospective birth cohort study with follow-up to the age of 15 years. Between December 1997-January 1999 parents attending one of 14 obstetrical clinics or hospitals throughout the cities of Munich, Leipzig, Wesel or Bad Honnef were invited to participate. A total of 3,095 healthy full term newborns whose parents were born in Germany and had German citizenship were recruited. Parental questionnaires were used to assess physician diagnosed asthma, allergic rhinitis and eczema; and episodes of wheezing at ages 0.5, 1, 1.5, 2, 4, 6 and 10 years (Gehring et al. 2002). Clinical examinations and blood samples for DNA extraction were obtained at 6 and 10 years.
The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a population based prospective birth cohort study, with an intervention component, and follow-up through the age of 15 years. Between May 1996 -December 1997, 3963 children were born to mothers who had been recruited during their first trimester of pregnancy from midwife practices in three different regions of The Netherlands. Children were divided into high-and low-risk groups based on a screening questionnaire on allergic disease of their mother. Children in the high-risk group were initially assigned to the intervention arm (n = 855) with a random subset allocated to the natural history arm (n = 472) with low-risk children. The intervention required use of a mite-impermeable mattress and pillow cover (Koopman et al. 2002). Information on physician-diagnosed asthma, allergic rhinitis and eczema; and episodes of wheezing were ascertained through parental questionnaires completed at each birthday until 8 years. Blood samples were collected at 4, 8, 11 and 12 years. Table S1. Association between ozone during the first year of life and asthma and wheeze at school age, stratified by genotype (pooled data, n = 2,743).